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- PDB-9g4s: Crystal structure of the human METTL3-METTL14 in complex with sma... -

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Basic information

Entry
Database: PDB / ID: 9g4s
TitleCrystal structure of the human METTL3-METTL14 in complex with small molecule inhibitor Compound 56
Components(N6-adenosine-methyltransferase ...) x 2
KeywordsRNA BINDING PROTEIN / METTL3 METTL14 inhibitor Epics
Function / homology
Function and homology information


negative regulation of hematopoietic progenitor cell differentiation / mRNA m6A methyltransferase / mRNA m(6)A methyltransferase activity / RNA N6-methyladenosine methyltransferase complex / positive regulation of cap-independent translational initiation / endothelial to hematopoietic transition / RNA methylation / regulation of meiotic cell cycle / RNA methyltransferase activity / primary miRNA processing ...negative regulation of hematopoietic progenitor cell differentiation / mRNA m6A methyltransferase / mRNA m(6)A methyltransferase activity / RNA N6-methyladenosine methyltransferase complex / positive regulation of cap-independent translational initiation / endothelial to hematopoietic transition / RNA methylation / regulation of meiotic cell cycle / RNA methyltransferase activity / primary miRNA processing / forebrain radial glial cell differentiation / dosage compensation by inactivation of X chromosome / oxidoreductase complex / S-adenosyl-L-methionine binding / gliogenesis / mRNA stabilization / mRNA modification / regulation of hematopoietic stem cell differentiation / regulation of neuron differentiation / regulation of T cell differentiation / negative regulation of type I interferon-mediated signaling pathway / oogenesis / stem cell population maintenance / mRNA destabilization / Processing of Capped Intron-Containing Pre-mRNA / negative regulation of Notch signaling pathway / positive regulation of translation / response to nutrient levels / mRNA splicing, via spliceosome / circadian rhythm / mRNA processing / cellular response to UV / spermatogenesis / nuclear speck / nuclear body / protein heterodimerization activity / innate immune response / mRNA binding / DNA damage response / Golgi apparatus / nucleoplasm / nucleus / cytosol
Similarity search - Function
N6-adenosine-methyltransferase non-catalytic subunit METTL14-like / mRNA (2'-O-methyladenosine-N(6)-)-methyltransferase-like (MT-A70-like) family profile. / N6-adenosine-methyltransferase MT-A70-like / mRNA (2'-O-methyladenosine-N(6)-)-methyltransferase (EC 2.1.1.62) family profile. / MT-A70-like / MT-A70 / MT-A70-like family profile. / S-adenosyl-L-methionine-dependent methyltransferase superfamily
Similarity search - Domain/homology
: / N(6)-adenosine-methyltransferase catalytic subunit METTL3 / N(6)-adenosine-methyltransferase non-catalytic subunit METTL14
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 Å
AuthorsDutheuil, G. / Oukoloff, K.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: To Be Published
Title: Crystal structure of the human METTL3-METTL14 in complex with small molecule inhibitor Compound 56
Authors: Dutheuil, G. / Oukoloff, K.
History
DepositionJul 16, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 12, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: N6-adenosine-methyltransferase catalytic subunit
B: N6-adenosine-methyltransferase non-catalytic subunit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,9759
Polymers57,1902
Non-polymers7857
Water5,603311
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5010 Å2
ΔGint-59 kcal/mol
Surface area21660 Å2
MethodPISA
Unit cell
Length a, b, c (Å)64.191, 64.191, 225.132
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number154
Space group name H-MP3221

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Components

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N6-adenosine-methyltransferase ... , 2 types, 2 molecules AB

#1: Protein N6-adenosine-methyltransferase catalytic subunit / Methyltransferase-like protein 3 / hMETTL3 / N6-adenosine-methyltransferase 70 kDa subunit / MT-A70


Mass: 24656.363 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: METTL3, MTA70 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q86U44, mRNA m6A methyltransferase
#2: Protein N6-adenosine-methyltransferase non-catalytic subunit / Methyltransferase-like protein 14 / hMETTL14


Mass: 32533.955 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: METTL14, KIAA1627 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9HCE5

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Non-polymers , 4 types, 318 molecules

#3: Chemical ChemComp-A1III / 4-[(3~{R})-3-(cyclopropylmethylamino)piperidin-1-yl]-1-[(1~{R})-1-[4-[5-(dimethylamino)pyridin-3-yl]-1,2,3-triazol-1-yl]ethyl]pyridin-2-one


Mass: 462.590 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H34N8O
#4: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Ca
#5: Chemical ChemComp-TRS / 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL / TRIS BUFFER


Mass: 122.143 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H12NO3 / Comment: pH buffer*YM
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 311 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.47 Å3/Da / Density % sol: 50.12 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 0.2 M calcium chloride, 0.1 M Tris:HCl pH 8.0, 18% (w/v) PEG 4000, 20C, sitting drop, protein:precipitant solution ratio = 1:1

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 1 / Wavelength: 0.97856 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Sep 8, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97856 Å / Relative weight: 1
ReflectionResolution: 1.95→45.03 Å / Num. obs: 38278 / % possible obs: 100 % / Redundancy: 11.7 % / CC1/2: 0.997 / Net I/σ(I): 8.8
Reflection shellResolution: 1.95→2 Å / Num. unique obs: 2921 / CC1/2: 0.96

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.95→44.71 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.93 / SU B: 4.896 / SU ML: 0.133 / Cross valid method: THROUGHOUT / ESU R: 0.173 / ESU R Free: 0.161 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24343 2043 5.1 %RANDOM
Rwork0.19502 ---
obs0.19753 38278 99.95 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 34.835 Å2
Baniso -1Baniso -2Baniso -3
1--0.11 Å2-0.05 Å2-0 Å2
2---0.11 Å20 Å2
3---0.35 Å2
Refinement stepCycle: 1 / Resolution: 1.95→44.71 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3819 0 47 311 4177
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0134053
X-RAY DIFFRACTIONr_bond_other_d0.0010.0173824
X-RAY DIFFRACTIONr_angle_refined_deg1.5451.6475515
X-RAY DIFFRACTIONr_angle_other_deg1.2571.5838812
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.5335485
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.43921.213239
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.46415695
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.0531537
X-RAY DIFFRACTIONr_chiral_restr0.0720.2514
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.024557
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02972
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it3.143.4461905
X-RAY DIFFRACTIONr_mcbond_other3.1413.4451904
X-RAY DIFFRACTIONr_mcangle_it4.9965.1242383
X-RAY DIFFRACTIONr_mcangle_other4.9955.1262384
X-RAY DIFFRACTIONr_scbond_it3.0643.7932148
X-RAY DIFFRACTIONr_scbond_other3.0563.7932148
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.8385.5613123
X-RAY DIFFRACTIONr_long_range_B_refined7.6939.2134567
X-RAY DIFFRACTIONr_long_range_B_other7.67439.0764523
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.95→2.001 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.323 157 -
Rwork0.332 2764 -
obs--100 %

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